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Blood Advances Jun 2024Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and...
Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.
Topics: Humans; Aminopterin; Lymphoma, T-Cell, Peripheral; Middle Aged; Male; Female; Aged; Adult; Aged, 80 and over; Treatment Outcome; Recurrence; Young Adult
PubMed: 38429077
DOI: 10.1182/bloodadvances.2023010441 -
Blood Advances Jan 2024Pralatrexate is a folate antagonist that selectively enters cells expressing reduced folate carrier type 1 and competitively inhibits dihydrofolate reductase, leading to...
Pralatrexate is a folate antagonist that selectively enters cells expressing reduced folate carrier type 1 and competitively inhibits dihydrofolate reductase, leading to interruption of RNA synthesis, DNA replication, and apoptosis. This phase 1 study was conducted to evaluate the maximum tolerated dose (MTD) of pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen (part 1) and the response and pharmacokinetics of 6 cycles of this combination (CHOP + Folotyn 30 mg/m2 [Fol-CHOP]) in patients with newly diagnosed peripheral T-cell lymphoma (PTCL). In part 1, on days 1 and 8 of each cycle, patients were treated with 10, 15, 20, 25, or 30 mg/m2 of pralatrexate in combination with CHOP, per dose escalation, in 5 sequential cohorts. No patients experienced DLTs in cohorts 1, 2, 3, 4, and 5. The pralatrexate dose of 30 mg/m2 was selected to be combined with CHOP for part 2 and administered to 33 additional patients in the expansion cohort. At the MTD, the Fol-CHOP regimen was generally well tolerated in patients with PTCL, with an overall response rate (ORR) of 83.9% (20 complete response and 6 partial response), as assessed by treating investigators. Thirty-five patients (67.3%) experienced grade 3/4 treatment-emergent adverse events, the most common of which were anemia (21.2%), neutropenia (19.2%), febrile neutropenia (11.5%), fatigue, mucosal inflammation, nausea, and vomiting (7.7% each). In conclusion, Fol-CHOP was found to be a safe and effective treatment for newly diagnosed PTCL and deemed worthy of further investigation. This trial was registered at www.ClinicalTrials.gov as #NCT02594267.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Aminopterin; Treatment Outcome; Fatigue
PubMed: 38029357
DOI: 10.1182/bloodadvances.2023011095 -
Journal of the Formosan Medical... Feb 2024We aimed to explore the clinical outcomes and prognostic factors for PTCL-NOS patients in the real world.
PURPOSE
We aimed to explore the clinical outcomes and prognostic factors for PTCL-NOS patients in the real world.
METHODS
Clinical data were retrospectively collected from adult patients with PTCL-NOS treated at a single center in Taiwan.
RESULTS
104 PTCL-NOS patients with a median age of 53.0 years were enrolled. Patients with the International Prognostic Index (IPI) or prognostic index for peripheral T-cell lymphoma (PIT) scores of zero had a longer overall survival (OS) and progression free survival (PFS), while patients with IPI or PIT scores ≥1 did poorly. For patients who are eligible for transplantation, the use of pralatrexate as salvage chemotherapy has shown better OS (2-year OS 83.3% vs. 24.4%, P = 0.011) compared to patients who did not. By multivariate analysis, age >60 years, male, B symptoms, ECOG >1, lung involvement, and thrombocytopenia were independent adverse factors for OS. Incorporating factors in multivariate analysis, we established a novel predictive index for PTCL-NOS which efficiently stratifies patients into low (0-1 factor), intermediate-1 (2 factors), intermediate-2 (3 factors), and high risk (4-6 factors) groups with 2-year OS rates of 81.5%, 32.9%, 8.8%, and 0%, respectively (P < 0.001).
CONCLUSION
PTCL-NOS patients have a dismal prognosis in Taiwan. Novel agents may improve the outcomes of PTCL-NOS patients. The usefulness of the novel prognostic index for PTCL-NOS needs further validation.
Topics: Humans; Male; Middle Aged; Lymphoma, T-Cell, Peripheral; Progression-Free Survival; Retrospective Studies; Treatment Outcome; East Asian People
PubMed: 37558588
DOI: 10.1016/j.jfma.2023.07.014 -
Viruses May 2023During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate...
During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.
Topics: Humans; SARS-CoV-2; COVID-19; Pandemics; Molecular Docking Simulation; Antiviral Agents; Drug Repositioning
PubMed: 37243214
DOI: 10.3390/v15051128 -
Indian Journal of Pharmacology 2022Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing...
Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R).
INTRODUCTION
Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein.
MATERIALS AND METHODS
Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
RESULTS AND DISCUSSION
Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better.
CONCLUSION
We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.
Topics: Binding Sites; Ligands; Linoleic Acid; Molecular Dynamics Simulation; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Antiviral Agents
PubMed: 36722555
DOI: 10.4103/ijp.ijp_111_22 -
Biomedicine & Pharmacotherapy =... Apr 2023Glioblastoma Multiforme (GBM) is known to be by far the most aggressive brain tumor to affect adults. The median survival rate of GBM patient's is < 15 months, while...
Glioblastoma Multiforme (GBM) is known to be by far the most aggressive brain tumor to affect adults. The median survival rate of GBM patient's is < 15 months, while the GBM cells aggressively develop resistance to chemo- and radiotherapy with their self-renewal capacity which suggests the pressing need to develop novel preventative measures. We have recently proved that GPR17 -an orphan G protein-coupled receptor- is highly expressed on the GBM cell surface and it has a vital role to play in the disease progression. Despite the progress made on GBM downregulation, there still remain difficulties in developing a promising modulator for GPR17, till date. Here, we have performed robust virtual screening combined with biased-force pulling molecular dynamic (MD) simulations to predict high-affinity GPR17 modulators followed by experimental validation. Initially, the database containing 1379 FDA-approved drugs were screened against the orthosteric binding pocket of the GPR17. The external bias-potentials were then applied to the screened hits during the MD simulations which enabled to predict a spectrum of rupture peak force values that were used to select four approved drugs -ZINC000003792417 (Sacubitril), ZINC000014210457 (Victrelis), ZINC000001536109 (Pralatrexate) and ZINC000003925861 (Vorapaxar)- as top hits. The hits selected turns out to demonstrate unique dissociation pathways, interaction pattern, and change in polar network over time. Subsequently the selected hits with GPR17 were measured by inhibiting the forskolin-stimulated cAMP accumulation in GBM cell lines, LN229 and SNB19. The ex vivo validations shows that Sacubitril drug can act as a full agonist, while Vorapaxar functions as a partial agonist for GPR17. The pEC of Sacubitril was identified as 4.841 and 4.661 for LN229 and SNB19, respectively. Small interference of the RNA (siRNA)- silenced the GPR17 to further validate the targeted binding of Sacubitril with GPR17. In the current investigation, we have identified new repurposable GPR17 specific drugs which are likely to increase the opportunity to treat orphan deadly diseases.
Topics: Humans; Receptors, G-Protein-Coupled; Lactones; Pyridines
PubMed: 36716660
DOI: 10.1016/j.biopha.2023.114320 -
Heliyon Dec 2022Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new...
Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% . This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.
PubMed: 36544829
DOI: 10.1016/j.heliyon.2022.e12064 -
Molecules (Basel, Switzerland) Sep 2022Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common... (Review)
Review
Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.
Topics: Antimetabolites; Folic Acid; Folic Acid Antagonists; Methotrexate; Pemetrexed; Quinazolines; Thiophenes
PubMed: 36234766
DOI: 10.3390/molecules27196229 -
Annals of Translational Medicine Jul 2022Multiple myeloma (MM) with t (11;14) has a unique biology. New combinations of novel agents are needed to improve the prognosis of patients with t (11;14) MM. As a...
BACKGROUND
Multiple myeloma (MM) with t (11;14) has a unique biology. New combinations of novel agents are needed to improve the prognosis of patients with t (11;14) MM. As a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), palbociclib (PAL) has been used to treat various malignancies, including breast cancer, ovarian cancer, and so on. However, the effects of PAL on MM remain unclear, and thus, further investigations are warranted.
METHODS
Two t (11;14) MM cell lines, U266 and KMS27, were used in this study. The cell viability and cell cycle were detected to evaluate the anti-myeloma effect of the combination of pralatrexate (PTX) and methotrexate (MTX) with PAL. Three-dimensional (3D) spheroid and mouse models were built to verify the effect of the combination treatment. Western blot was used to detect the expressions of Minichromosome Maintenance Complex Component 2 (MCM2), Minichromosome Maintenance Complex Component 3 (MCM3), and dihydrofolate reductase (DHFR).
RESULTS
It was observed that PAL had obvious anticancer effects on U266 and KMS27 cells, which had synergistic effects together with PTX and MTX. Importantly, it was found that PAL could promote cell cycle genes including MCM2 and MCM3, and increase the number of MM cells in the G1 phase. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on MM cells by targeting DHFR. It was also determined that PAL exerted anticancer effects on MM in the spheroid and mouse models.
CONCLUSIONS
PAL exerted obvious anticancer effects on t (11;14) MM cells, which had synergistic effects together with PTX and MTX. PAL could promote cell cycle genes and the G1 phase of MM cells. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on t (11;14) MM cells by targeting DHFR.
PubMed: 35957711
DOI: 10.21037/atm-22-2830 -
Frontiers in Chemistry 2022Desired drug candidates should have both a high potential binding chance and high specificity. Recently, many drug screening strategies have been developed to screen...
Desired drug candidates should have both a high potential binding chance and high specificity. Recently, many drug screening strategies have been developed to screen compounds with high possible binding chances or high binding affinity. However, there is still no good solution to detect whether those selected compounds possess high specificity. Here, we developed a reverse DFCNN (Dense Fully Connected Neural Network) and a reverse docking protocol to check a given compound's ability to bind diversified targets and estimate its specificity with homemade formulas. We used the RNA-dependent RNA polymerase (RdRp) target as a proof-of-concept example to identify drug candidates with high selectivity and high specificity. We first used a previously developed hybrid screening method to find drug candidates from an 8888-size compound database. The hybrid screening method takes advantage of the deep learning-based method, traditional molecular docking, molecular dynamics simulation, and binding free energy calculated by metadynamics, which should be powerful in selecting high binding affinity candidates. Also, we integrated the reverse DFCNN and reversed docking against a diversified 102 proteins to the pipeline for assessing the specificity of those selected candidates, and finally got compounds that have both predicted selectivity and specificity. Among the eight selected candidates, Platycodin D and Tubeimoside III were confirmed to effectively inhibit SARS-CoV-2 replication with EC values of 619.5 and 265.5 nM, respectively. Our study discovered that Tubeimoside III could inhibit SARS-CoV-2 replication potently for the first time. Furthermore, the underlying mechanisms of Platycodin D and Tubeimoside III inhibiting SARS-CoV-2 are highly possible by blocking the RdRp cavity according to our screening procedure. In addition, the careful analysis predicted common critical residues involved in the binding with active inhibitors Platycodin D and Tubeimoside III, Azithromycin, and Pralatrexate, which hopefully promote the development of non-covalent binding inhibitors against RdRp.
PubMed: 35903186
DOI: 10.3389/fchem.2022.933102